CN112441969A - Selective sodium channel regulator and preparation and application thereof - Google Patents

Selective sodium channel regulator and preparation and application thereof Download PDF

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CN112441969A
CN112441969A CN202010889003.0A CN202010889003A CN112441969A CN 112441969 A CN112441969 A CN 112441969A CN 202010889003 A CN202010889003 A CN 202010889003A CN 112441969 A CN112441969 A CN 112441969A
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unsubstituted
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pain
compound
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姚元山
李傲
P·K·贾达夫
曹国庆
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Minghui Pharmaceutical Hangzhou Co ltd
Minghui Pharmaceutical Shanghai Co ltd
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Minghui Pharmaceutical Hangzhou Co ltd
Minghui Pharmaceutical Shanghai Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Abstract

The invention provides an alternativeThe invention provides a compound of a selective sodium channel regulator and a synthesis and use method thereof, in particular to a compound shown as a formula (I), a preparation method thereof and application thereof as the selective sodium channel regulator. The compounds exhibit excellent activity as sodium channel modulators.

Description

Selective sodium channel regulator and preparation and application thereof
Technical Field
The invention relates to a compound as a selective sodium channel regulator, an isomer, a solvate, a salt of the compound, a medicament taking the compound or the salt as an active ingredient, and application thereof in medicaments for treating and/or preventing target diseases related to sodium channel regulation, such as pain.
Background
Pain is a protective mechanism that protects healthy animals from tissue damage and prevents further damage to the damaged tissue. Nevertheless, there are many cases where pain persists beyond its usefulness, or where patients would benefit from pain suppression.
Neuropathic pain is a form of chronic pain caused by injury to sensory nerves, and can be divided into two categories, pain caused by injury to nerve metabolism and pain caused by injury to nerve continuity. Metabolic injury pain indications include post-herpetic neuropathy, diabetic neuropathy and drug-induced neuropathy. The pain indications caused by the continuous damage of the nerve comprise nerve entrapment injuries such as amputation pain, postoperative nerve injury pain and neuropathic back pain.
Voltage-gated sodium channels (Nav's) are involved in pain signaling. Nav are biological mediators of electrical signal transduction because they mediate the rapid ascending of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells). The role of these channels in normal physiology, pathological states caused by mutations in the sodium channel genes, preclinical work in animal models, and evidence of the clinical pharmacology of known sodium channel modulators suggest a central role for Nav's in pain perception. Nav's mediate the rapid upward movement of action potentials of many excitable cell types (e.g., neurons, skeletal muscle cells, cardiac muscle cells) and are therefore involved in the initiation of signaling in these cells. Antagonists that reduce Nav's current may prevent or reduce neural signals due to the role of Nav's in the initiation and propagation of neuronal signals, and Nav's are considered a possible target for pain relief where hyperexcitability is observed. Several clinically useful analgesics have been identified as inhibitors of Nav's. Local anesthetics such as lidocaine block pain by inhibiting Nav channels, and other compounds such as carbamazepine, lamotrigine and tricyclic antidepressants have been shown to be effective in relieving pain by sodium channel inhibition.
Nav's form voltage-gated ion channel superfamily subfamily, and contain 9 isoforms, named Nav1.1-Nav1.9. The tissue localization of the nine isoforms varied. Nav1.4 is skeletal muscle of the main sodium channel, Nav1.5 is myocardial cells of the main sodium channel. Nav 1.7, 1.8 and 1.9 mainly located in the peripheral nervous system, while Nay 1.1, 1.2, 1.3 and 1.6 is central and peripheral nervous system found in the neural channel. The functional behavior of the nine isoforms is similar, but differs in specific aspects of voltage-dependent and kinetic behavior.
The Nav1.8 channel is determined as a possible target for analgesia, and is proved to be a carrier of sodium current, maintains action potential emission of neurons in small dorsal root ganglia, and also participates in spontaneous signal emission of damaged neurons, such as driving neuropathic pain and the like. A major drawback of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isoform selectivity. Since Navl.8 is primarily restricted to pain-sensing neurons, selective Nav1.8 blockers are unlikely to induce the adverse effects common to non-selective Nav's blockers. Therefore, the field still needs to develop new Nav1.8 selective inhibitors.
Disclosure of Invention
The invention aims to provide a Nav1.8 selective inhibitor.
In a first aspect of the present invention, there is provided a compound represented by the following formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure BDA0002656354760000021
L1selected from the group consisting of: NR (nitrogen to noise ratio)4CO、CONR4Or SO2NR4；
L2Selected from the group consisting of: s (O)p，O，NR4CO or C (R)6)2；
Cyc1 and Cyc2 are each independently selected from: a 6-membered aryl, a 5-6-membered heteroaryl, and at least one of Cyc1 and Cyc2 is a 5-6-membered heteroaryl, the heteroatoms of which are independently selected from O, N or S (O)p；
R1Selected from: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)q-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, NOr S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a 5-6 membered heterocyclic or carbocyclic ring;
R2selected from: 0 to 4R1Substituted C3-C8 cycloalkyl, 0-4R1Substituted C4-C8 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R3selected from: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Nitro, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR4An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C4-C8 heterocyclyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, said heteroatoms independently selected from O, N or S (O)p；
R4Selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR4An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C4-C8 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two R4And the N atom to which it is attached form a C4-C8 membered heterocyclic ring;
n is selected from: 0, 1,2,3 or 4;
p is selected from: 0, 1 or 2;
R5selected from: XCON (R)4)2，CON(R4)2，NR4COR4Cyano, at least one R5Selected from CON (R)4)2Or NR4COR4；
X is selected from: o or NR4；
m is selected from: 2,3 or 4;
R6selected from: hydrogen, halogenAn amide group, a cyano group, a hydroxyl group, an amino group, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted- (W)q-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl; or two R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
w is selected from the group consisting of: CH (CH)2，NR4O, and at the same time only 2W are selected from the group: the content of N, O,
q is selected from: 0, 1,2,3, 4, 5 or 6;
in each of the above formulae, the heterocyclyl or heteroaryl groups each independently include 1,2, or 3 heteroatoms independently selected from O, N, or S (O)p；
Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
In another preferred embodiment, at least one of Cyc1 and Cyc2 is a 5-6 membered heteroaryl.
In another preferred embodiment, R5Selected from XCON (R)4)2，CON(R4)2，NR4COR4Or cyano, and at least one R5Selected from CON (R)4)2Or NR4COR4；
X is selected from: o or NR4；
In another preferred embodiment, R is5Is NR4COR4。
In another preferred embodiment, R is5Is CON (R)4)2。
In another preferred embodiment, the compound of formula (I) has the structure shown in formula (II) below:
Figure BDA0002656354760000041
wherein G is CH or N, and when G is CH, the CH can be replaced by R1Substituted (i.e., R)1Located on G).
In another preferred embodiment, L is1Is CONH, and/or said L2Is O.
In another preferred embodiment, the compound has the structure shown in the following formula (III):
Figure BDA0002656354760000042
wherein Ra, Rb, Rc and Rd are independently selected from the following groups: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted- (L)m-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl.
In another preferred embodiment, Ra, Rb, Rc and Rd are each independently selected from the group consisting of: hydrogen, deuterium, halogen, CF3，CD3，OCF3，OCH3，OCD3，CN。
In another preferred embodiment, the Cyc2 ring is a benzene ring or pyridine ring.
In another preferred embodiment, the compound of formula (I) has the structure shown in formula (IV) below:
Figure BDA0002656354760000051
wherein A is N or CR8And said R is8Selected from the group consisting of: H. f or R5；
And when A is N, R3Can form N with A+-O-。
In another preferred embodiment, the compound of formula (I) has a structure as shown in formula (V):
Figure BDA0002656354760000052
in another preferred embodiment, the compound is selected from the group consisting of:
Figure BDA0002656354760000053
Figure BDA0002656354760000061
in a second aspect of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to the first aspect of the invention.
In another preferred embodiment, the pharmaceutical composition is used in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
In another preferred embodiment, the treatment comprises reducing the severity of pain in the patient.
In another preferred embodiment, the neuropathic pain comprises post-herpetic neuralgia.
In another preferred embodiment, the neuropathic pain comprises idiopathic small-fiber neuropathy.
In another preferred embodiment, the musculoskeletal pain comprises osteoarthritis pain.
In another preferred embodiment, the acute pain comprises acute post-operative pain.
In another preferred embodiment, the post-operative pain comprises a bunion removal pain or an abdominoplasty pain.
In a third aspect of the invention, there is provided a use of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a pharmaceutical composition for the treatment, alleviation or prevention of a disease associated with sodium channel modulation; preferably, the disease or condition is pain.
In another preferred embodiment, the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly found a compound represented by the formula (I). The compounds have unexpected activity in modulating cytokines and/or interferons and are useful in the treatment of diseases mediated by cytokines and/or interferons. The compounds have unexpected activity on Nav1.8 and excellent selectivity on other Navs subtypes, and can be used for treating, relieving or preventing Nav 1.8-related diseases. Based on the above findings, the inventors have completed the present invention.
Definition of
As used herein, the term "alkyl" includes straight or branched chain alkyl groups. E.g. C1-C4Alkyl represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
As used herein, the term "C3-C8Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Also bicyclic, e.g., bridged, fused or spiro forms.
As used herein, the term "C6-C10Aryl "means an aryl group having 6 to 10 carbon atoms, for example, phenyl or naphthyl and the like.
As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to a cyclic aromatic group having 5-10 atoms and wherein 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be a single ring or a condensed ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) -triazolyl and (1,2,4) -triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
Unless specifically stated to be "substituted or unsubstituted", the groups of the present invention may be substituted with a substituent selected from the group consisting of: halogen, nitrile group, nitro group, hydroxyl group, amino group, C1-C6Alkyl-amino, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, halo C1-C6Alkyl, halo C2-C6Alkenyl, halo C2-C6Alkynyl, halo C1-C6Alkoxy, allyl, benzyl, C6-C12Aryl radical, C1-C6alkoxy-C1-C6Alkyl radical, C1-C6Alkoxy-carbonyl, phenoxycarbonyl, C2-C6Alkynyl-carbonyl, C2-C6Alkenyl-carbonyl, C3-C6Cycloalkyl-carbonyl, C1-C6Alkyl-sulfonyl, and the like.
As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br. "halogenated" means substituted with an atom selected from F, Cl, Br, and I.
Unless otherwise specified, the structural formulae depicted herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configuration containing an asymmetric center, (Z), (E) isomers of double bonds, and the like. Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations of the specific embodiments with other chemical synthetic methods, and equivalents known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The solvent used in the present application can be commercially available. Abbreviations used in this application are as follows: aq represents an aqueous solution; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; dMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; cbz represents benzyloxycarbonyl, an amino protecting group; boc represents tert-butyloxycarbonyl, an amino protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; THF represents tetrahydrofuran; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; boc2O represents di-tert-butyl dicarbonate; LDA stands for lithium diisopropylamide.
The compound is artificially processed or Chem
Figure BDA0002656354760000091
The software names, and the commercial compounds are under the supplier catalog name.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent activity as a sodium channel modulator, the compound of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment (stabilization, alleviation or cure) of a disease or disorder associated with a sodium channel, such as pain and the like.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 1-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and derivatives thereofBiological (such as sodium carboxymethylcellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, pulvis Talci, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifier (such as sodium carboxymethylcellulose, sodium ethyl cellulose, etc.), and other adjuvants
Figure BDA0002656354760000092
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, parenteral (intravenous, intramuscular, subcutaneous or topical).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of such other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately or sequentially with a compound of the invention for the prevention and/or treatment of cytokine and/or interferon mediated diseases.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 2000mg, preferably 1 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
Example 1
Figure BDA0002656354760000111
Figure BDA0002656354760000121
First step of
Compound 1a (10.00g, 38.90mmol) and potassium carbonate (16.10g, 116.72mmol) were dissolved in N, N-dimethylformamide (100mL) under nitrogen, and methyl iodide (8.30g, 58.35mmol) was added and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, water (50mL) was added to quench the reaction, ethyl acetate (50mL) was added, the mixture was separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1b (12.00g) in yield: 99 percent.
1H NMR(400MHz,DMSO-d6)δ7.66(dd,J＝8.7,0.4Hz,1H),7.10(d,J＝2.6Hz,1H),6.91–6.84(m,1H),3.85(s,3H).
Second step of
To a solution of compound 1b (12.00g, 44.28mmol) in tetrahydrofuran (100mL) was slowly added dropwise a solution of n-butyllithium in tetrahydrofuran (2.5M, 20mL, 0.50mmol) under nitrogen at-78 ℃. Stirring was continued for 30 minutes after the addition was complete. Triisopropyl borate (11.66g, 62.00mmol) was added dropwise to the above reaction solution at-78 ℃ and reacted at this temperature for 2 hours. After the reaction was completed, the pH was adjusted to 4-5 with 1N hydrochloric acid (60mL), ethyl acetate (50mL) was added, the layers were separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1c (6.00g), yield: 42 percent.
1H NMR(400MHz,CDCl3)δ7.85(d,J＝8.2Hz,1H),6.88(d,J＝8.2Hz,1H),6.72(s,1H),5.78(s,2H),3.93(s,3H).
The third step
To a solution of compound 1c (6.00g, 25.53mmol), sodium hydroxide (1.50g, 38.3mmol), sodium bicarbonate (21.40g, 255.32mmol), acetone (100mL) and ethylenediaminetetraacetic acid (745mg, 2.6mmol) in water (100mL) at 0 deg.C was added oxone complex salt (18.17g, 28.1mmol), then warmed to room temperature and stirred for 2 hours. After the reaction was completed, the pH was adjusted to acidity with 2N hydrochloric acid (180mL), ethyl acetate (100mL) was added for liquid separation, the aqueous phase was extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1d (2.30g), yield: 43 percent
1H NMR(400MHz,CDCl3)δ6.87(d,J＝8.4Hz,1H),6.73(d,J＝10.4Hz,2H),3.88(d,J＝0.6Hz,3H).
The fourth step
1e (200mg, 0.93mmol) was dissolved in methanol (10mL), and wet palladium on carbon (10%, 40mg) was added at room temperature to replace hydrogen (hydrogen pressure: 15psi) and reacted at room temperature for 4 hours. After completion of the reaction, celite was filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 1f (150mg) in yield: 88 percent.
1H NMR(400MHz,DMSO-d6)δ7.61(s,1H),7.39(s,1H),7.30(d,J＝8.2Hz,1H),7.17(s,1H),6.90(s,1H),6.48(m,2H),5.58(s,2H).
The fifth step
To a solution of compound 1g (5g, 27.31mmol) in dry tetrahydrofuran (50mL) was slowly added dropwise lithium diisopropylamide (2.0M in THF, 15mL, 30.00mmol) at-78 deg.C under nitrogen, and after the addition was complete, stirring was continued at-78 deg.C for 30 min. A solution of ethyl chloroformate (3.84g, 35.38mmol) in dry tetrahydrofuran (10mL) was added dropwise slowly to the above reaction mixture. After the dropwise addition, the obtained reaction solution was stirred at-78 ℃ for 40 minutes, and then naturally warmed to room temperature for further reaction for 1 hour. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution (50mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated saline solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to obtain 1h (3.10g), yield: 45 percent.
1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),4.42(d,J＝7.1Hz,2H),1.30(t,J＝7.1Hz,3H).
The sixth step
To a solution of 1h (340mg, 1.35mmol) and 1d (280mg, 1.35mmol) in N, N-dimethylformamide (10mL) was added cesium carbonate (877mg, 2.69mmol) at 0 deg.C under nitrogen. The reaction mixture was reacted at this temperature for 1.5 hours, and then allowed to spontaneously warm to room temperature. After completion of the reaction, water (20mL) and ethyl acetate (30mL) were added, liquid separation was performed, ethyl acetate (30mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 0 to 100%) to obtain 1i (300mg), yield: 51 percent.
1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.31(d,J＝8.8Hz,1H),7.11(d,J＝2.3Hz,1H),7.00-6.93(m,1H),4.40(dt,J＝8.6,6.4Hz,2H),3.79(s,3H),1.35(td,J＝7.1,1.6Hz,3H).
Seventh step
To a mixed solution of 1i (300mg, 0.68mmol) of tetrahydrofuran (15mL) and water (15mL) was added sodium hydroxide (135mg, 3.38mmol) in portions at 0 ℃ under nitrogen. After the addition was complete, the reaction was allowed to warm to room temperature and the reaction was continued for 2 hours. After the reaction was completed, the pH was adjusted to about 2 with 1N dilute hydrochloric acid, dichloromethane (30mL x3) was extracted, the organic phases were combined, washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 1j (290 mg).
1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.21(d,J＝8.4Hz,1H),6.87(s,2H),3.78(s,3H).
Eighth step
To a 1j (100mg, 0.24mmol) solution in N, N-dimethylformamide (2mL) under nitrogen atmosphere were added 1f (43mg, 0.24mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (137mg, 0.36mmol) and N, N-diisopropylethylamine (93mg, 0.72mmol) in that order. The resulting reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, water (20mL) and ethyl acetate (30mL) were added to the reaction solution, followed by liquid separation, extraction with ethyl acetate (20mL × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 1(78mg), yield: 53 percent.
MS-ESI calculated value [ M +1 ]]+577, found 577.
1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.11(s,1H),7.76(s,1H),7.70-7.65(m,3H),7.53(d,J＝9.0Hz,1H),7.35(dd,J＝17.3,12.8Hz,3H),7.23(d,J＝2.4Hz,1H),7.00(d,J＝9.8Hz,1H),3.77(s,3H).
Example 2
Figure BDA0002656354760000151
First step of
To compound 2a (200mg, 1.09mmol) in dry tetrahydrofuran (5mL) was slowly added lithium diisopropylamide (0.55mL, 1.20mmol) dropwise under nitrogen at-78 ℃. After stirring at this temperature for 30 minutes after the completion of the dropwise addition, a solution of ethyl chloroformate (154mg, 1.43mmol) in dry tetrahydrofuran (10mL) was added dropwise. The reaction mixture was stirred at-78 ℃ for 40 minutes, then allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, the reaction mixture was quenched with a saturated ammonium chloride solution (20mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated saline solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give compound 2b (30mg) in yield: 12 percent.
1H NMR(400MHz,DMSO-d6)δ8.01(dd,J＝14.4,8.5Hz,1H),7.43(t,J＝9.0Hz,1H),4.43–4.30(m,2H),1.34–1.22(m,3H).
Second step of
Compound 2b (4.00g, 15.74mmol) was dissolved in methanol (40mL), and 1N aqueous sodium hydroxide solution (40mL) was added. The reaction was stirred at room temperature for 2 hours under nitrogen. After the reaction, 6N hydrochloric acid was added to the reaction mixture to adjust the pH to about 1, water (60mL) was added to dilute the reaction mixture, ethyl acetate (100mL × 3) was extracted, the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2c (1.50g), yield: 38 percent.
1H NMR(400MHz,DMSO-d6)δ7.99(dd,J＝14.4,8.5Hz,1H),7.42(t,J＝8.9Hz,1H).
The third step
Compound 2c (2.00g, 8.85mmol), cesium carbonate (5.77g, 17.70mmol) and iodomethane (2.51g, 17.70mmol) were dissolved in N, N-dimethylformamide (100mL), and the mixture was stirred at room temperature for 2 hours while displacing nitrogen. Water (60mL) was added for dilution, ethyl acetate (100mL × 3) was extracted, the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2d (1.50g), yield: 70 percent.
MS-ESI calculated value [ M +1 ]]+241, measured value 241.
The fourth step
2d (1.50g, 6.25mmol) and 1d (1.30g, 6.25mmol) were dissolved in N, N-dimethylformamide (10mL), and cesium carbonate (4.07g, 12.50mmol) was added under ice bath. The reaction system was stirred and reacted for 1.5 hours under ice bath with nitrogen substitution three times, warmed to room temperature, added with water (20mL) and ethyl acetate (30mL), separated, the aqueous phase was extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate ═ 0-100%) to give 2e (1.20g), yield: 45 percent.
MS-ESI calculated value [ M +1 ]]+429, found 429.
The fifth step
2e (1.20g, 2.80mmol) was dissolved in a mixed solvent of tetrahydrofuran (15mL) and water (15mL), and sodium hydroxide (561mg, 14.02mmol) was added in portions under ice-bath conditions, and after replacing nitrogen, the reaction system was warmed to room temperature and stirred for 2 hours. Adjusted to pH about 2 with 1N dilute hydrochloric acid, extracted with dichloromethane (30mL x3), combined organic phases, washed with saturated brine (20mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2f (800mg), yield: and 69 percent.
MS-ESI calculated value [ M +1 ]]+415, found value 415.
The sixth step
2g (2.00g, 9.47mmol) was dissolved in N, N-dimethylformamide (50mL), and ammonium chloride (1.52g, 28.42mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (10.80g, 28.42mmol), N, N-diisopropylethylamine (6.10g, 47.35mmol) were added thereto, followed by nitrogen substitution three times, and after stirring at room temperature for 2 hours, concentration under reduced pressure was directly performed to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain 2h (200mg) in yield: 10 percent.
Seventh step
After 2h (200mg, 0.96mol) was dissolved in tetrahydrofuran (5mL), 10% wet palladium on carbon (20mg) was added to replace hydrogen (15psi) three times, and the mixture was stirred at room temperature for 1 hour, the reaction was directly filtered and concentrated under reduced pressure to give 2i (150mg), yield: 87 percent.
Eighth step
2f (116mg, 0.28mmol), 2i (50mg, 0.28mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (160mg, 0.42mmol), N-diisopropylethylamine (108mg, 0.84mmol) was added thereto, the mixture was replaced with nitrogen three times, stirred at room temperature for 2 hours, and then directly concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give compound 2(4mg) in yield: 3 percent.
MS-ESI calculated value [ M +1 ]]+576, found: 576.
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.23(s,2H),8.04(s,1H),7.96(s,2H),7.75(t,J＝8.7Hz,1H),7.45(s,2H),7.33(d,J＝8.8Hz,1H),7.23(s,1H),7.02(d,J＝7.8Hz,1H),6.61(d,J＝8.9Hz,1H),3.76(s,3H).
example 3
Figure BDA0002656354760000171
First step of
3a (200mg, 1.28mmol) was dissolved in tetrahydrofuran (10mL) and triethylamine (337mg, 3.33mmol) was added. After purging with nitrogen, methyl chloroformate (315mg, 3.33mmol) was added dropwise under ice bath. Stir at room temperature for 2 hours, filter, and concentrate under reduced pressure to give crude 3b (350 mg).
MS-ESI calculated value [ M +1 ]]+273, found value: 273.
second step of
3b (350mg, 1.28mmol) was dissolved in tetrahydrofuran (5mL) and heavy water (5mL), and after adding sodium deuteroborohydride (268mg, 6.40mmol) at room temperature with replacement of nitrogen, it was stirred at room temperature for 2 hours. Extraction with ethyl acetate (20mL x3) under ice-bath, organic phase combination, drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure gave a residue which was subjected to column chromatography (ethyl acetate: petroleum ether ═ 0-100%) to give 3c (150mg) in two steps: 91 percent.
The third step
Compound 3c (150mg, 1.16mmol) was dissolved in N, N-dimethylformamide (10mL), added for 1h (296mg, 1.16mmol), and then cesium carbonate (757mg, 2.32mmol) was added to the reaction system under ice bath, and the reaction system was stirred for 2h under ice bath. After completion of the reaction, filtration and concentration under reduced pressure gave a residue, which was subjected to column chromatography (ethyl acetate: petroleum ether ═ 0 to 100%) to give 3d (100mg) in yield: 24 percent.
MS-ESI calculated value [ M +1 ]]+365, found: 365.
1H NMR(400MHz,CDCl3)δ11.28(s,1H),8.33(s,1H),8.00(s,1H),7.02(s,1H),4.52(q,J＝7.3Hz,2H),1.45(t,J＝7.2Hz,3H).
the fourth step
Compound 3d (200mg, 0.55mmol) was dissolved in tetrahydrofuran (10mL) and water (10mL), and sodium hydroxide (268mg, 6.40mmol) was added portionwise at room temperature, replaced with nitrogen three times, and then stirred at room temperature overnight. pH was adjusted to about 2 with 2N hydrochloric acid, extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 3e (90mg), yield: 49 percent.
MS-ESI calculated value [ M +1 ]]+337, found: 337.
the fifth step
After 3d (100mg, 0.30mmol) was dissolved in N, N-dimethylformamide (10mL), the compound 1f (64mg, 0.36mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (170mg, 0.45mmol), N-diisopropylethylamine (115mg, 0.89mmol) were added, then nitrogen substitution was carried out three times, stirring was carried out at room temperature for 2 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 3(12mg) in yield: 8 percent.
MS-ESI calculated value [ M +1 ]]+498, found 498.
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.07(s,1H),7.77(s,1H),7.67(t,J＝8.9Hz,3H),7.53(d,J＝8.8Hz,1H),7.33(d,J＝16.6Hz,2H),7.22(d,J＝8.6Hz,2H),7.12(d,J＝8.5Hz,1H).
Example 4
Figure BDA0002656354760000191
First step of
1j (83mg, 0.22mmol), 2c (40mg, 0.22mmol) were dissolved in N, N-dimethylformamide (5mL), and 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (114mg, 0.30mmol), N-diisopropylethylamine (65mg, 0.50mmol) was further added, followed by nitrogen substitution three times, stirring was performed at room temperature for 2 hours, and then concentration was performed under reduced pressure to obtain a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to obtain example 4(6mg), yield: 5 percent.
MS-ESI calculated value [ M +1 ]]+577, found value: 577.
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.18(s,2H),8.11(s,1H),8.08(s,1H),7.98(s,2H),7.48(s,2H),7.38(d,J＝9.0Hz,1H),7.22(s,1H),6.99(d,J＝9.6Hz,1H),3.78(s,3H).
example 5
Figure BDA0002656354760000201
First step of
After 5a (1.00g, 3.84mmol) was dissolved in methanol (10mL), aqueous ammonia (269mg, 7.69mmol) was added and nitrogen was substituted three times, the reaction was stirred at 70 ℃ for 2 hours. The reaction solution was filtered to obtain a white solid, i.e., 5b (867mg), yield: 92 percent.
MS-ESI calculated value [ M +1 ]]+245, found: 245.
second step of
5b (867mg, 3.54mmol) was dissolved in absolute ethanol (10mL) and water (10mL), ammonium chloride (1.89g, 35.39mmol) and iron powder (990mg, 17.69mmol) were added thereto at room temperature, nitrogen gas was replaced three times, and the mixture was heated to 80 ℃ and stirred for 3 hours. Filtration and concentration under reduced pressure gave a residue which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 5c (612mg), yield: 80 percent.
MS-ESI calculated value [ M +1 ]]+215, found: 215.
the third step
After dissolving 5c (100mg, 0.47mmol) in N, N-dimethylformamide (5mL), 1j (162mg, 0.39mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (225mg, 0.59mmol), N-diisopropylethylamine (151mg, 1.17mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 5d (157mg) in yield: 66 percent.
MS-ESI calculated value [ M +1 ]]+612, found: 612.
the fourth step
After 5d (150mg, 0.25mmol) was dissolved in N, N-dimethylformamide (5mL), cuprous cyanide (88mg, 0.98mmol) and tetratriphenylphosphine palladium (28mg, 0.03mmol) were added, followed by three nitrogen replacements, stirring at 120 ℃ for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 5(3mg) in yield: 2 percent.
MS-ESI calculated value [ M +1 ]]+559, found: 559.
1H NMR(400MHz,CD3OD)δ8.09(s,1H),8.03(s,1H),7.93(s,2H),7.33(d,J＝8.7Hz,1H),7.07(s,1H),6.93(s,1H),3.80(s,3H).
example 6
Figure BDA0002656354760000211
First step of
After 6a (500mg, 2.42mmol) was dissolved in methanol (10mL) and 10% wet palladium on carbon (50mg) was added to replace hydrogen, the reaction was stirred at room temperature for 2 hours. The reaction solution was filtered through celite, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane 0-100%) to give 6b (200mg) in yield: 46 percent.
MS-ESI calculated value [ M +1]+177, found: 177.
second step of
After 6b (350mg, 0.84mmol) was dissolved in N, N-dimethylformamide (15mL), 1j (140mg, 0.79mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (383mg, 1.00mmol), N-diisopropylethylamine (325mg, 2.52mmol) were further added, followed by nitrogen substitution three times, stirring at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography under reduced pressure to give a residue, which was purified (ethyl acetate: petroleum ether ═ 0-100%) to give 6c (210mg) yield: and 43 percent.
MS-ESI calculated value [ M +1 ]]+574, found: 574.
the third step
6c (210mg, 0.36mmol) was dissolved in aqueous ammonia (10mL), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give 6d (140mg), yield: 46 percent.
MS-ESI calculated value [ M +1 ]]+592, found: 592.
the fourth step
After 6d (140mg, 0.23mmol) was dissolved in N, N-dimethylformamide (10mL), ammonium chloride (14mg, 0.25mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (114mg, 0.30mmol), N-diisopropylethylamine (91mg, 0.69mmol) were added, then nitrogen substitution was carried out three times, stirring was carried out at room temperature for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid separation was carried out, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography under reduced pressure to give a residue, which was purified (ethyl acetate: petroleum ether ═ 0-100%) to give 6(50mg) yield: and 43 percent.
MS-ESI calculated value [ M +1 ]]+591, found: 591.
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.23–8.09(m,2H),7.69(s,1H),7.52-7.48(m,1H),7.38(d,J＝8.7Hz,1H),7.31(d,J＝18.9Hz,1H),7.24(s,1H),7.01(d,J＝8.7Hz,1H),3.77(s,3H),2.68(d,J＝3.8Hz,3H).
example 7
Figure BDA0002656354760000231
First step of
After 7a (1.00g, 3.84mmol) was dissolved in methanol (10mL), aqueous ammonia (269mg, 7.69mmol) was added and nitrogen was substituted three times, the reaction was stirred at 70 ℃ for 2 hours. The reaction solution was filtered to obtain a white solid, i.e., 7b (867mg), yield: 92 percent.
MS-ESI calculated value [ M +1 ]]+245, found: 245.
second step of
7b (867mg, 3.54mmol) was dissolved in a mixed solution of absolute ethanol (10mL) and water (10mL), ammonium chloride (1.89g, 35.39mmol) and iron powder (990mg, 17.69mmol) were added at room temperature and replaced with nitrogen three times, and the mixture was stirred at 80 ℃ for 3 hours. Filtering, concentrating the filtrate under reduced pressure to obtain residue, and subjecting the residue to column chromatography (methanol: dichloro)Methane0-100%) to give 7c (612mg), yield: 80 percent.
MS-ESI calculated value [ M +1 ]]+215, found: 215.
the third step
After dissolving 7c (100mg, 0.47mmol) in N, N-dimethylformamide (5mL), 1j (162mg, 0.39mmol), 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (225mg, 0.59mmol), N-diisopropylethylamine (151mg, 1.17mmol) were added and then replaced with nitrogen three times, and after stirring at room temperature for 3 hours, water (30mL) and ethyl acetate (30mL) were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0-100%) to give 7d (157mg) in yield: 66 percent.
MS-ESI calculated value [ M +1 ]]+612, found: 612.
the fourth step
7d (150mg, 0.25mmol) was dissolved in N, N-dimethylformamide (5mL), cuprous cyanide (88mg, 0.98mmol) and tetratriphenylphosphine palladium (28mg, 0.03mmol) were added, nitrogen was substituted three times, and after stirring at 120 ℃ for 2 hours, water (60mL) and ethyl acetate (60mL) were added, liquid was separated, the aqueous phase was extracted with ethyl acetate (20mL × 3), organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography (methanol: dichloromethane ═ 0 to 100%) to give 7(3mg) in yield: 2 percent.
MS-ESI calculated value [ M +1 ]]+559, found: 559.
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.41(s,1H),8.17(d,J＝14.7Hz,1H),7.71(s,2H),7.37(d,J＝8.6Hz,1H),7.21(s,1H),6.99(s,1H),3.76(s,3H).
biological activity assay
The in vitro inhibition effect of the compound on Nav1.8 was tested on HEK293 cells stably expressing human Nav1.8 using a manual patch clamp assay. Test compounds were dissolved in DMSO to prepare 9mM stock solutions, which were dissolved in extracellular fluid at the desired concentration on the day of testing. The extracellular fluid component comprises (mM) NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4(NaOH titration). Cells were clamped at-80 mV and then depolarized to 10mV with a square wave lasting 10 milliseconds to give a NaV1.8 current. This procedure is repeated every 5 seconds. And detecting the maximum current caused by the square wave, perfusing a test compound (dissolved in extracellular fluid according to the required concentration) after the maximum current is stabilized, and calculating the blocking strength of the compound to Nav1.8 according to the current strength before and after the compound is perfused after the reaction is stabilized. Data collection and analysis were performed using pCLAMP 10(Molecular Devices, Union City, Calif.), and current stabilization means that the current varies over time within a limited range. The test results are shown in the following tables-1 and-2.
Inhibitory Activity of the Compounds of Table-1 on Nav1.8
Compound numbering IC50(nM)
Example 1 0.5
TABLE-2 The% blockade of Nav1.8 channels at a concentration of 4nM of the compound
Figure BDA0002656354760000251
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (11)

1. A compound of formula (I), and isomers, solvates or pharmaceutically acceptable salts thereof:
Figure RE-FDA0002837356690000011
L1selected from the group consisting of: NR (nitrogen to noise ratio)4CO、CONR4Or SO2NR4；
L2Selected from the group consisting of: s (O)p，O，NR4CO or C (R)6)2；
Cyc1 and Cyc2 are each independently selected from: a 6-membered aryl, a 5-6-membered heteroaryl, and at least one of Cyc1 and Cyc2 is a 5-6-membered heteroaryl, the heteroatoms of which are independently selected from O, N or S (O)p；
R1Selected from: hydrogen, deuterium, ═ O, halogen, CHF2，CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4Substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)q-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two adjacent R1And the atoms to which they are attached form a 5-6 membered heterocyclic or carbocyclic ring;
R2selected from: 0 to 4R1Substituted C3-C8 cycloalkyl, 0-4R1Substituted C4-C8 heterocyclyl, 0-4R1Substituted 6-10 membered aryl, 0-4R1Substituted 5-10 membered heteroaryl; or two adjacent R1And the atoms to which they are attached form a 5-6 membered carbocyclic or heterocyclic ring;
R3selected from: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Nitro, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR4An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C4-C8 heterocyclyl group, a substituted or unsubstituted 6-10 membered aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group, said heteroatoms independently selected from O, N or S (O)p；
R4Selected from: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, 1 or 2 nonadjacent carbon atoms being replaced by O or NR4An alternative C1-C6 alkyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C4-C8 heterocyclyl group, said heteroatoms independently selected from O, N or S (O)p(ii) a Or two R4And the N atom to which it is attached form a C4-C8 membered heterocyclic ring;
n is selected from: 0, 1,2,3 or 4;
p is selected from: 0, 1 or 2;
R5selected from: XCON (R)4)2，CON(R4)2，NR4COR4Cyano, and at least one R5Selected from CON (R)4)2Or NR4COR4；
X is selected from: o or NR4；
m is selected from: 2,3 or 4;
R6selected from: hydrogen, halogen, amido, cyano, hydroxy, amino, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted- (W)q-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl; or two R6And the atoms to which they are attached form a carbocyclic ring of C3-C8 or a heterocyclic ring of C4-C8;
w is selected from the group consisting of: CH (CH)2，NR4O, and at the same time only 2W are selected from the group: n R4，O，
q is selected from: 0, 1,2,3, 4, 5 or 6;
in each of the above formulae, the heterocyclyl or heteroaryl groups each independently include 1,2, or 3 heteroatoms independently selected from O, N, or S (O)p；
Unless otherwise specified, "substituted" means substituted with one or more (e.g., 2,3, 4, etc.) substituents selected from the group consisting of: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, amide, sulfonamide, sulfone; a group selected from the group consisting of unsubstituted or substituted with one or more substituents: a C6-C10 aryl group, a halogenated C6-C10 aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, a halogenated 5-10 membered heterocyclyl group having 1-3 heteroatoms selected from N, S and O, and said substituents are selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 alkoxy, ═ O.
2. The compound of claim 1, wherein at least one of Cyc1 and Cyc2 is a 5-6 membered heteroaryl.
3. A compound according to claim 1 to 2, wherein R is5Selected from XCON (R)4)2，CON(R4)2，NR4COR4Or cyano, and at least one R5Selected from CON (R)4)2Or NR4COR4；
X is selected from: o or NR4。
4. A compound according to any one of claims 1 to 3, wherein the compound of formula (I) has the structure shown in formula (II):
Figure RE-FDA0002837356690000031
wherein G is CH or N, and when G is CH, the CH can be replaced by R1Substituted (i.e., R)1Located on G).
5. The compound of claims 1-4, wherein L is1Is CONH, and/or said L2Is O.
6. The compound of claims 1-5, wherein the compound has the structure of formula (III):
Figure RE-FDA0002837356690000032
wherein Ra, Rb, Rc and Rd are independently selected from the following groups: hydrogen, deuterium, ═ O, halogen, CF3，CD3，OCF3，OCH3，OCD3Cyano, nitro, hydroxy, amino, SO2N(R4)2，CON(R4)2，COOR4Substituted or unsubstitutedC1-C6 alkyl, substituted or unsubstituted- (W)q-H, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C4-C8 heterocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl.
7. The compound of claim 1, wherein said compound is selected from the group consisting of:
Figure RE-FDA0002837356690000033
Figure RE-FDA0002837356690000041
Figure RE-FDA0002837356690000051
8. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, isomer, solvate or pharmaceutically acceptable salt or hydrate thereof according to claims 1 to 6.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is for use in a method of treating, ameliorating or preventing a disease or disorder associated with sodium channel modulation; preferably, the disease or condition is pain.
10. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or hydrate thereof, for the preparation of a pharmaceutical composition for the treatment, alleviation or prevention of diseases associated with sodium channel modulation; preferably, the disease or condition is pain.
11. The use according to claim 10, wherein the pain or disease is selected from the group consisting of: chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, post-operative pain, visceral pain, multiple sclerosis, peroneal muscular atrophy (Charcot-Marie-Tooth syndrome), incontinence, pathological cough, or cardiac arrhythmia.
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